Results from studies proposed for the first three years of this grant have shown that urine pH is a major determinant of the renal clearance of fluoride. The rate is increased by an alkaline pH and depressed by an acid pH. These results are relevant to the cariostatic effect of fluoride because balance, and not merely intake, is the key variable. Other studies were completed and the results of these indicated that tramsmembrane pH gradients may be important in several aspects of fluoride metabolism and toxicity. The studies proposed for the next three years will continue to explore the mechanism(s) of fluoride transport and distribution and the impact which variations in acid-base status and urine pH have on fluoride metabolism and toxicity. The characteristics of transport and distribution will be studied using red blood cells, the kidney and ureter, the oral mucosa and selected soft tissues. Two of the proposed studies will evaluate the effects of mild chronic acid-base disturbances induced by altitude and diet on the body-wide metabolism of fluoride in laboratory animals. Persons living at high altitudes exhibit a chronic respiratory alkalosis and should have a less positive fluoride balance than persons living at lower altitudes. Infants fed cows' milk based formulae tend to be acidotic, relative to breast-fed infants, and should exhibit a relatively positive fluoride balance. Therefore, in addition to furthering our understanding of the characteristics and mechanisms of fluoride metabolism, these studies may reveal factors leading to the discovery of populations which require special consideration in terms of the amounts of fluoride provided them.